William Wetsel - Academia.edu (original) (raw)

Papers by William Wetsel

Brain Research, Aug 1, 2022

bioRxiv (Cold Spring Harbor Laboratory), Oct 7, 2022

ACS Chemical Neuroscience, Apr 8, 2021

Metrics & More Article Recommendations T he authors would like to include citation of patent lite... more Metrics & More Article Recommendations T he authors would like to include citation of patent literature to provide a more comprehensive record for syntheses of the chemical scaffolds described in this research article. 1 Syntheses of compounds 10, 13, 27, 30, 32, and 38 in the published article are covered by these patent applications. 2−4

Biological Psychiatry, May 1, 2020

Alzheimer's & Dementia, 2020

NMR in Biomedicine, Nov 23, 2022

The United States is experiencing a dramatic increase in maternal opioid misuse and, consequently... more The United States is experiencing a dramatic increase in maternal opioid misuse and, consequently, the number of individuals exposed to opioids in utero. Prenatal opioid exposure has both acute and long‐lasting effects on health and wellbeing. Effects on the brain, often identified at school age, manifest as cognitive impairment, attention deficit, and reduced scholastic achievement. The neurobiological basis for these effects is poorly understood. Here, we examine how in utero exposure to heroin affects brain development into early adolescence in a mouse model. Pregnant C57BL/6J mice received escalating doses of heroin twice daily on gestational days 4–18. The brains of offspring were assessed on postnatal day 28 using 9.4 T diffusion MRI of postmortem specimens at 36 μm resolution. Whole‐brain volumes and the volumes of 166 bilateral regions were compared between heroin‐exposed and control offspring. We identified a reduction in whole‐brain volume in heroin‐exposed offspring and heroin‐associated volume changes in 29 regions after standardizing for whole‐brain volume. Regions with bilaterally reduced standardized volumes in heroin‐exposed offspring relative to controls include the ectorhinal and insular cortices. Regions with bilaterally increased standardized volumes in heroin‐exposed offspring relative to controls include the periaqueductal gray, septal region, striatum, and hypothalamus. Leveraging microscopic resolution diffusion tensor imaging and precise regional parcellation, we generated whole‐brain structural MRI diffusion connectomes. Using a dimension reduction approach with multivariate analysis of variance to assess group differences in the connectome, we found that in utero heroin exposure altered structure‐based connectivity of the left septal region and the region that acts as a hub for limbic regulatory actions. Consistent with clinical evidence, our findings suggest that prenatal opioid exposure may have effects on brain morphology, connectivity, and, consequently, function that persist into adolescence. This work expands our understanding of the risks associated with opioid misuse during pregnancy and identifies biomarkers that may facilitate diagnosis and treatment.

ACS Chemical Neuroscience, Aug 6, 2019

Dopamine receptors are important G protein-coupled receptors (GPCRs) with therapeutic opportuniti... more Dopamine receptors are important G protein-coupled receptors (GPCRs) with therapeutic opportunities for treating Parkinson's Disease (PD) motor and cognitive deficits. Biased D 1 dopamine ligands that differentially activate G protein over β-arrestin recruitment pathways are valuable chemical tools for dissecting positive versus negative effects in drugs for PD. Here, we reveal an iterative approach toward modification of a D 1-selective noncatechol scaffold critical for *

Human Molecular Genetics, Dec 26, 2018

The 16p11.2 BP4-BP5 deletion and duplication syndromes are associated with a complex spectrum of ... more The 16p11.2 BP4-BP5 deletion and duplication syndromes are associated with a complex spectrum of neurodevelopmental phenotypes that includes developmental delay and autism spectrum disorder, with a reciprocal effect on head circumference, brain structure and body mass index. Mouse models of the 16p11.2 copy number variant have recapitulated some of the patient phenotypes, while studies in f lies and zebrafish have uncovered several candidate contributory genes within the region, as well as complex genetic interactions. We evaluated one of these loci, KCTD13, by modeling haploinsufficiency and complete knockout in mice. In contrast to the zebrafish model, and in agreement with recent data, we found normal brain structure in heterozygous and homozygous mutants. However, recapitulating previously observed genetic interactions, we discovered sex-specific brain volumetric alterations in double heterozygous Kctd13xMvp and Kctd13xLat mice. Behavioral testing revealed a significant deficit in novel object recognition, novel location recognition and social transmission of food preference in Kctd13 mutants. These phenotypes were concomitant with a reduction in density of mature spines in the hippocampus, but potentially independent of RhoA abundance, which was unperturbed postnatally in our mutants. Furthermore, transcriptome analyses from cortex and hippocampus highlighted the dysregulation of pathways important in neurodevelopment, the most significant of which was synaptic formation. Together, these data suggest that KCTD13 contributes to the neurocognitive aspects of patients with the BP4-BP5 deletion, likely through genetic interactions with other loci.

Cell, May 1, 2021

Highlights d Engineered psychLight-a genetically encoded 5-HT sensor based on the 5-HT2AR d Psych... more Highlights d Engineered psychLight-a genetically encoded 5-HT sensor based on the 5-HT2AR d PsychLight can measure 5-HT dynamics in behaving mice d A psychLight-based cellular imaging platform predicts hallucinogenic potential d Identified a non-hallucinogenic psychedelic analog with antidepressant properties

Scientific Reports, Mar 1, 2019

As discussion of stress and stress-related disorders rapidly extends beyond the brain, gut microb... more As discussion of stress and stress-related disorders rapidly extends beyond the brain, gut microbiota have emerged as a promising contributor to individual differences in the risk of illness, disease course, and treatment response. Here, we employed chronic mild social defeat stress and 16S rRNA gene metagenomic sequencing to investigate the role of microbial composition in mediating anxiety-and depressive-like behavior. In socially defeated animals, we found significant reductions in the overall diversity and relative abundances of numerous bacterial genera, including Akkermansia spp., that positively correlated with behavioral metrics of both anxiety and depression. Functional analyses predicted a reduced frequency of signaling molecule pathways, including G-protein-coupled receptors, in defeated animals. Collectively, our data suggest that shifts in microbial composition may play a role in the pathogenesis of anxiety and depression. Major depressive disorder (MDD) is a debilitating and stigmatized public health concern. While recognized as a leading cause of disability worldwide and affecting up to 16% of the population, definitive mechanisms underlying the pathophysiology of MDD remain unknown 1-3. Enabled by the emergence of molecular and metagenomic technologies, the focus of mental health has rapidly extended to include not only the central nervous system, but also its connection to and communication with the periphery, namely the gut microbiome. Unsurprisingly, given the high comorbidity between gastrointestinal disorders and depression, studies have revealed that patients with MDD have an altered microbial composition 4-6. This finding has been recapitulated in various animal models as exposure to social stressors known to elicit anxiety-and depressive-like behavior have been shown to produce alterations in the structure of gut microbial communities 7-11. However, the microbiota-gut-brain axis is bidirectional. Not only are anxiety and depression reflected in microbial composition, but evidence suggests that microbiota can influence brain function and behavior 4,12-15. Colonization of germ-free mice with 'depressive' fecal microbiota from patients with MDD has produced depressive-like behaviors compared to colonization with 'healthy' microbiota from control subjects 4. As such, the composition of gut microbial communities becomes an increasingly recognized environmental factor contributing to individual differences in risk of illness, disease course, and treatment response. This study investigated whether exposure to stress disrupted gut microbiota in a preclinical model of depression. We used 16S rRNA gene sequencing to examine shifts in bacterial communities resulting from a mild social

ACS pharmacology & translational science, Dec 30, 2022

Advances in Experimental Medicine and Biology, 1987

Recently, the sequence of the cDNA which encodes the LHRH-prohormone was elucidated from human pl... more Recently, the sequence of the cDNA which encodes the LHRH-prohormone was elucidated from human placenta and human and rat hypothalamus and the corresponding amino acid sequence deduced (Seeburg et al., 1984 and Adelman et al., 1986). In addition to LHRH, the prohormone contains a 56 amino acid sequence, designated gonadotropin-releasing hormone associated peptide (GAP), which is attached to the C-terminus of the LHRH decapep-tide. Although not yet confirmed, the human GAP sequence has been reported to possess both gonadotropin-releasing and prolactin inhibiting activity (Nikolics et al., 1985). Additionally, a 13-amino acid fragment of the human GAP sequence (proLHRH 14–26) has been reported to stimulate gonadotropin release (Millar et al., 1986). Regardless of whether the non-LHRH portion of the LHRH prohormone contains biological activity, this sequence can serve as a valuable marker for studies of LHRH prohormone synthesis, processing and degradation. In order to initiate these types of studies, we have generated specific antisera (MC-1, 2 and 3) against a fragment of the human GAP sequence (proLHRH 38–66) and developed a radioimmunoassay procedure for the quantitation of GAP (Culler and Negro-Vilar, 1986). The antisera are specific for midportion sequences of the GAP molecule and do not cross-react with any other known brain peptide.

The FASEB Journal, Sep 10, 2020

Small ubiquitin‐like modifier (SUMO1‐3) conjugation (SUMOylation), a posttranslational modificati... more Small ubiquitin‐like modifier (SUMO1‐3) conjugation (SUMOylation), a posttranslational modification, modulates almost all major cellular processes. Mounting evidence indicates that SUMOylation plays a crucial role in maintaining and regulating neural function, and importantly its dysfunction is implicated in cognitive impairment in humans. We have previously shown that simultaneously silencing SUMO1‐3 expression in neurons negatively affects cognitive function. However, the roles of the individual SUMOs in modulating cognition and the mechanisms that link SUMOylation to cognitive processes remain unknown. To address these questions, in this study, we have focused on SUMO2 and generated a new conditional Sumo2 knockout mouse line. We found that conditional deletion of Sumo2 predominantly in forebrain neurons resulted in marked impairments in various cognitive tests, including episodic and fear memory. Our data further suggest that these abnormalities are attributable neither to constitutive changes in gene expression nor to alterations in neuronal morphology, but they involve impairment in dynamic SUMOylation processes associated with synaptic plasticity. Finally, we provide evidence that dysfunction on hippocampal‐based cognitive tasks was associated with a significant deficit in the maintenance of hippocampal long‐term potentiation in Sumo2 knockout mice. Collectively, these data demonstrate that protein conjugation by SUMO2 is critically involved in cognitive processes.

Endocrinology, Nov 1, 1993

gamma-Aminobutyric acid (GABA) has been shown both to stimulate and inhibit LH secretion in vivo.... more gamma-Aminobutyric acid (GABA) has been shown both to stimulate and inhibit LH secretion in vivo. GABA apparently exerts these effects at the hypothalamic level by regulating the release of LHRH. In this study, we have investigated the effect of GABAergic agents on LHRH secretion from an immortalized hypothalamic neuronal cell line (GT1-7). LHRH secretion was stimulated in a dose-dependent manner with increasing concentrations of GABA. This effect was mimicked by the GABAA receptor agonist, muscimol, and was blocked by the selective antagonist, bicuculline. The stimulatory effect of muscimol on LHRH secretion was synergistic with low concentrations of [K+]. By comparison, neither activation of the GABAB receptors with baclofen nor blockade with phaclofen influenced basal LHRH secretion. Baclofen, however, did depress [K+]-induced LHRH release. Binding studies confirmed the presence of GABAA and GABAB receptors on GT1-7 cells. In addition, Northern blots with probes to the GABAA receptor alpha 1, beta 3, and gamma 2L subunits revealed that only the beta 3 messenger RNA (mRNA) was expressed in the GT1-7 cells. These data provide the first demonstration that immortalized LHRH neurons are directly responsive to GABAergic agents. To the extent that these immortalized neurons may resemble those in vivo, our results suggest that GABAergic agents may play a dual role in reproductive physiology by exerting both stimulatory and inhibitory control over LHRH release.

Elsevier eBooks, 1989

Publisher Summary This chapter discusses the combined antibody-high-performance liquid chromatogr... more Publisher Summary This chapter discusses the combined antibody-high-performance liquid chromatography approach to assess prohormone processing. This approach creates special problems for the protein biochemist and physiologist because the amino acid sequences of the various peptides may not be known with certainty (the peptide has not been sequenced, only deduced from a complementary DNA (cDNA)), the regulatory steps involved in the biosynthesis, processing, and secretion of the peptides are unclear, and their functional roles are often unexplored. Various tissues may metabolize the same precursor peptides by different routes, and these products may have different functional consequences depending on the locus of secretion and the physiological/pathological status of the organism. These circumstances emphasize the importance of adopting a coordinated and multifaceted approach in detailing a peptide's fate from biosynthesis to function. Perhaps, through additional biochemical and physiological manipulations, we will be able to dissect more clearly the contribution of different gonadal factors to the biosynthesis, processing, transport, secretion, and/or degradation of these various processed products from luteinizing hormone releasing hormone (LHRH) neurons.

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2012

Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate c... more Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and non-canonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side-effects of drugs. However, few such ligands have been created and very little purposeful attention has been devoted to studying what we term: 'structure-functional selectivity relationships' (SFSR). We recently disclosed the first β-arrestin-biased dopamine D 2 receptor (D 2 R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these β-arrestin-biased D 2 R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered.

Scientific Reports, Dec 11, 2022

Genetically tractable animal models provide needed strategies to resolve the biological basis of ... more Genetically tractable animal models provide needed strategies to resolve the biological basis of drug addiction. Intravenous self-administration (IVSA) is the gold standard for modeling psychostimulant and opioid addiction in animals, but technical limitations have precluded the widespread use of IVSA in mice. Here, we describe IVSA paradigms for mice that capture the multi-stage nature of the disorder and permit predictive modeling. In these paradigms, C57BL/6J mice with long-standing indwelling jugular catheters engaged in cocaine-or remifentanil-associated lever responding that was fixed ratio-dependent, dose-dependent, extinguished by withholding the drug, and reinstated by the presentation of drug-paired cues. The application of multivariate analysis suggested that drug taking in both paradigms was a function of two latent variables we termed incentive motivation and discriminative control. Machine learning revealed that vulnerability to drug seeking and relapse were predicted by a mouse's a priori response to novelty, sensitivity to drug-induced locomotion, and drugtaking behavior. The application of these behavioral and statistical-analysis approaches to geneticallyengineered mice will facilitate the identification of neural circuits driving addiction susceptibility and relapse and focused therapeutic development. Abbreviations IVSA Intravenous self-administration i.p. Intraperitoneal FR Fixed ratio EFA Exploratory factor analyses Drug overdose is the leading cause of injury-related mortality in the U.S., claiming more than 70,000 lives in 2017 alone 1 and costing an estimated $78.5 billion per year in healthcare, lost productivity, and criminal justice involvement 2. While synthetic opioids, including fentanyl and its derivatives, are responsible for the spike in overdose deaths in recent years, mortality associated with cocaine and methamphetamine use disorders also tripled between 2012 and 2016 3. Available therapies for opioid use disorders are inadequate, and there are no Food and Drug Administration (FDA)-approved therapies for the treatment of stimulant use disorders. This paucity of treatments persists despite a medical consensus that opioid and stimulant addictions are brain disorders and, as such, should be amenable to pharmacological interventions 4. The lack of effective therapeutics may be due to chemical addictions being a family of disorders whose multiple etiologies remain ill-defined. An understanding of the genetic and molecular determinants of addiction-associated behaviors will facilitate the identification of therapeutic targets and at-risk individuals. Animal studies permit levels of control and manipulations that are unfeasible with human subjects. Multiple paradigms, with varying levels of complexity, exist for modeling the effects of drug use in animals. Intravenous

Journal of comparative neurology, Oct 15, 1993

Protein kinase C (PKC) is one of the major cellular signal transduction systems. Since at least n... more Protein kinase C (PKC) is one of the major cellular signal transduction systems. Since at least nine different PKC isoenzymes have been described, the purpose of the present studies was to identify the regional, cellular, and subcellular distributions of PKCδ in the rat central nervous system (CNS) by light and electron microscopic immunocytochemistry. We have found that PKCδ immunoreactivity is present in all major subdivisions of the rat CNS. Within each of the subdivisions, PKCδ immunoreactivity is localized to perikarya that monitor sensory and motor functions. More specifically, PKCδ is found in the olfactory bulb, cerebral cortex, lateral septum, thalamus, vestibular and cochlear nuclei, inferior olive, nucleus of the solitary tract, cerebellum, and superficial layers of the dorsal horn in the spinal cord. In most cases, the distribution of this isoenzyme is distinct from that of the conventional isoforms. Within the CNS, PKCδ is localized primarily in neurons; however, neurons of the same type are not uniformly labeled. This is most evident in the cerebellum, where alternating columns of Purkinje cells are immunostained. While PKCδ is prominent in perikarya, occasional immunostaining is seen in dendrites, fibers or axons, and nerve terminals. Electron microscopic analysis of the posterolateral nucleus of the thalamus reveals that the cell nucleus, the rough endoplasmic reticulum, and the plasma membrane are all immunopositive. Since each of the PKC subspecies may have different substrate, lipid, and other co‐factor requirements, the regional, cellular, and subcellular distribution of each of these isoforms should help to define their functional environments. © 1993 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.